Primeiro artigo revisto por pares sobre o protocolo Coimbra na revista internacional “Frontiers in immunology.
O estudo foi conduzido pelos médicos alemães do protocolo, Dr. Lemke e Dr. Schweiger em colaboração com o Prof. Jörg Spitz.
“Resistência à vitamina D como uma possível causa de doenças autoimunes: uma hipótese confirmada por um protocolo terapêutico de vitamina D em altas doses:
(…) A necessidade de altas doses de vitamina D3 para o sucesso do tratamento pode ser explicada pelo conceito de uma forma adquirida de resistência à vitamina D. Sua etiologia é baseada, por um lado, em polimorfismos dentro de genes que afetam o sistema da vitamina D e causam suscetibilidade ao desenvolvimento de baixa responsividade à vitamina D e doenças autoimunes; por outro lado, é baseado no bloqueio da sinalização do receptor da vitamina D, por exemplo, por infecções por patógenos.
Neste artigo, revisamos as evidências observacionais e mecanicistas para a hipótese de resistência à vitamina D adquirida. Em particular, centramo-nos na sua confirmação clínica a partir da nossa experiência no tratamento de pacientes com esclerose múltipla com o denominado protocolo Coimbra, em que doses diárias até 1000 UI de vitamina D3 por kg de peso corporal pode ser administrada com segurança.
Nesse contexto, os níveis séricos do hormônio da paratireóide fornecem as informações essenciais para a escolha da dose certa. Argumentamos que a resistência adquirida à vitamina D representa um patomecanismo plausível para o desenvolvimento de doenças autoimunes que poderiam ser tratadas com terapia com altas doses de vitamina D3.
(…) Atualmente, não existem terapias causais e, portanto, confiáveis para corrigir o bloqueio do VDR. A única terapia eficaz até o momento é o protocolo de altas doses de vitamina D, conhecido como protocolo Coimbra, em homenagem ao seu inventor (30). Até aproximadamente 1000 UI de vitamina D3 por kg de peso corporal, isso envolve as mais altas doses terapêuticas de vitamina D iniciais para o tratamento da EM. Para outras doenças autoimunes, doses muito mais baixas parecem ser suficientes (Tabela 1).
A hipercalcemia pode ser uma grande preocupação levantada contra este protocolo. No entanto, conforme discutido em mais detalhes abaixo, a resistência à vitamina D parece conferir proteção intrínseca contra a hipercalcemia. Além disso, a terapia exige que o paciente tome alguns cuidados. Além de evitar laticínios e manter uma ingestão mínima de líquidos de 2,5 L / dia, os pacientes devem monitorar de forma consistente vários parâmetros sanguíneos e passar por exames ultrassonográficos regulares dos rins. Na prática, isso requer um contato próximo e regular com um médico certificado pelo protocolo Coimbra.
(…) O protocolo Coimbra segue uma longa tradição médica de compensar a resistência do receptor com doses mais elevadas.
(…) Sob supervisão de um médico experiente (protocolo Coimbra), as altas doses de vitamina D3 aplicadas não causam hipercalcemia ou danos renais. Eles exercem apenas efeitos fisiológicos – por exemplo, a resistência à vitamina D subjacente tem um efeito protetor contra uma dose normalmente classificada como potencialmente tóxica.
(…) Essas melhorias subjetivas em pacientes com doenças autoimunes, bem como dados de segurança, também foram coletados na rede de médicos do Protocolo de Coimbra na Alemanha; estes serão o assunto de futuras publicações.”
Artigo completo:
Vitamin D3 (cholecalciferol) is a secosteroid and prohormone which is metabolized in various tissues to the biologically most active vitamin D hormone 1,25(OH)2D3 (calcitriol). 1,25(OH)2D3 has multiple pleiotropic effects, particularly within the immune system, and is increasingly utilized not only within prophylaxis, but also within therapy of various diseases. In this context, the latest research has revealed clinical benefits of high dose vitamin D3 therapy in autoimmune diseases. The necessity of high doses of vitamin D3 for treatment success can be explained by the concept of an acquired form of vitamin D resistance. Its etiology is based on the one hand on polymorphisms within genes affecting the vitamin D system, causing susceptibility towards developing low vitamin D responsiveness and autoimmune diseases; on the other hand it is based on a blockade of vitamin D receptor signaling, e.g. through pathogen infections. In this paper, we review observational and mechanistic evidence for the acquired vitamin D resistance hypothesis. We particularly focus on its clinical confirmation from our experience of treating multiple sclerosis patients with the so-called Coimbra protocol, in which daily doses up to 1000 I.U. vitamin D3 per kg body weight can be administered safely. Parathyroid hormone levels in serum thereby provide the key information for finding the right dose. We argue that acquired vitamin D resistance provides a plausible pathomechanism for the development of autoimmune diseases, which could be treated using high-dose vitamin D3 therapy.
Introduction
Vitamin D is a secosteroid and prohormone which can be obtained from food (as either vitamin D2 or D3), but whose main source is endogenous production in the skin. This requires ultraviolet-B radiation (290-315 nm) of at least 18 mJ/cm2 intensity (1), inducing the formation of previtamin D3 from 7-dehydrocholesterol which subsequently converts to vitamin D3 (cholecalciferol) by body heat (2). Upon reaching the blood, vitamin D3 mainly binds to vitamin-D binding protein (DBP) and gets transported to the liver where it is transformed into its storage form calcidiol (25-hydroxyvitamin D3 or 25(OH)D3) through hydroxylation via the vitamin D3 25-hydroxylases CYP2R1, CYP27A1 or CYP27B1, all members of the cytochrome P450 enzyme family (3, 4). 25(OH)D3 is the main laboratory parameter to judge an individual’s vitamin D status; concentrations <20 ng/ml (1ng/ml = 2,5 nmol/l) are considered as vitamin D deficiency, and 40-60 ng/ml as ideal (2, 5). 25(OH)D3 is metabolized in various tissues (predominantly the kidneys) to the biologically most active vitamin D hormone calcitriol (1,25-dihydroxyvitamin D or 1,25(OH)2D3) with another hydroxylation at the 1α position by CYP27A1 or CYP27B1 (3, 4). Besides regulating calcium metabolism, 1,25(OH)2D3 has multiple pleiotropic effects, particularly within the immune system, and is increasingly utilized not only within prophylaxis, but also within therapy of various diseases (2, 6, 7). In particular, binding of 1,25(OH)2D3 to the vitamin D receptor (VDR) has been shown to inhibit the differentiation and proliferation of B and T helper (Th) lymphocytes, promoting the shift of an inflammatory to a more tolerant immune status which may explain the protective effects of vitamin D against autoimmune diseases [reviewed in (8)].
More recently, Slominski and colleagues have revealed alternative pathways of vitamin D metabolism mediated by the mitochondrial enzyme CYP11A1 which is able to hydroxylate the side chain of vitamin D2/D3 (9–11). The main product of these reactions is 20-hydroxyvitamin D3 (20(OH)D3), which has a 20-30-fold lower concentration than 25(OH)D3 in human serum (9, 11) and is the initial substrate for the formation of further hydroxy-derivatives such as 20,23(OH)2D3, 17,20,23(OH)3D3 or 20,22(OH)2D3 [reviewed in (12)]. These nonclassical vitamin D metabolites also act as hormones: besides being partial agonists of the VDR, they have high affinity as agonists of the aryl hydrocarbon receptor (AhR) (13) and as inverse agonists of the retinoid-related orphan receptors (ROR) α and γ (14, 15). Notably, CYP11A1 is expressed in immune cells (16) and RORα and RORγ are expressed by inflammatory Th17 cells in which they synergistically regulate differentiation and inflammatory cytokine production (17). Th17-derived cytokines, notably interleukin (IL)17, have been implicated in the etiology of autoimmune disorders such as psoriasis (18) and multiple sclerosis (MS) (19). In addition, single nucleotide polymorphisms (SNPs) of the RORA gene have been associated with MS (20). The binding of 1,25(OH)2D3, 20(OH)D and other vitamin D hydroxy-metabolites to both RORα and RORγ, result in IL17 inhibition (14), thus providing another mechanism distinct from VDR signaling how vitamin D may protect from, or alleviate symptoms of, autoimmune diseases.
For approximately 15 years, patients with autoimmune diseases, particularly MS, have been successfully treated using a high-dose vitamin D protocol. Because this method has been developed by Prof. Dr. Cicero Coimbra in Sao Paolo, Brazil, it is frequently referred to as the “Coimbra protocol”; in Germany it is utilized since 2016. Underlying the Coimbra protocol is the hypothesis of a non-hereditary, but acquired form of vitamin D resistance which this paper is going to examine.
A hallmark of acquired vitamin D resistance, if it exists, would be an elevated parathyroid hormone (PTH) concentration despite 25(OH)D3 levels being in the ideal range and thus indicating sufficient production of 1,25(OH)2D3. One key role of 1,25(OH)2D3 is to enhance intestinal calcium absorption. If ionized calcium concentrations in blood are low, the parathyroid glands release PTH which stimulates calcium release from bones. Furthermore, PTH increases the conversion of 25(OH)D3 into 1,25(OH)2D3 in the kidneys with subsequent release into circulation. PTH also inhibits the tubular reabsorption of phosphate which in turn lowers the amount of water-insoluble calcium-phosphate salts and thus increases ionized calcium concentrations. In this way, PTH constitutes a direct feedback mechanism within the vitamin D system. A physiological 25(OH)D3 level should thereby be able to suppress PTH into the lower third of the reference range. In other words: If 25(OH)D3 levels are high, PTH should be low and vice versa. In patients with autoimmune diseases this negative feedback loop is disturbed. Based on these observations, Prof. Coimbra proposed the hypothesis of a vitamin D resistance.
The Hypothesis of Acquired Vitamin D Resistance (continua)
Vitamin D3 (cholecalciferol) is a secosteroid and prohormone which is metabolized in various tissues to the biologically most active vitamin D hormone 1,25(OH)2D3 (calcitriol). 1,25(OH)2D3 has multiple pleiotropic effects, particularly within the immune system, and is increasingly utilized not only within prophylaxis, but also within therapy of various diseases. In this context, the latest research has revealed clinical benefits of high dose vitamin D3 therapy in autoimmune diseases. The necessity of high doses of vitamin D3 for treatment success can be explained by the concept of an acquired form of vitamin D resistance. Its etiology is based on the one hand on polymorphisms within genes affecting the vitamin D system, causing susceptibility towards developing low vitamin D responsiveness and autoimmune diseases; on the other hand it is based on a blockade of vitamin D receptor signaling, e.g. through pathogen infections. In this paper, we review observational and mechanistic evidence for the acquired vitamin D resistance hypothesis. We particularly focus on its clinical confirmation from our experience of treating multiple sclerosis patients with the so-called Coimbra protocol, in which daily doses up to 1000 I.U. vitamin D3 per kg body weight can be administered safely. Parathyroid hormone levels in serum thereby provide the key information for finding the right dose. We argue that acquired vitamin D resistance provides a plausible pathomechanism for the development of autoimmune diseases, which could be treated using high-dose vitamin D3 therapy.
Introduction
Vitamin D is a secosteroid and prohormone which can be obtained from food (as either vitamin D2 or D3), but whose main source is endogenous production in the skin. This requires ultraviolet-B radiation (290-315 nm) of at least 18 mJ/cm2 intensity (1), inducing the formation of previtamin D3 from 7-dehydrocholesterol which subsequently converts to vitamin D3 (cholecalciferol) by body heat (2). Upon reaching the blood, vitamin D3 mainly binds to vitamin-D binding protein (DBP) and gets transported to the liver where it is transformed into its storage form calcidiol (25-hydroxyvitamin D3 or 25(OH)D3) through hydroxylation via the vitamin D3 25-hydroxylases CYP2R1, CYP27A1 or CYP27B1, all members of the cytochrome P450 enzyme family (3, 4). 25(OH)D3 is the main laboratory parameter to judge an individual’s vitamin D status; concentrations <20 ng/ml (1ng/ml = 2,5 nmol/l) are considered as vitamin D deficiency, and 40-60 ng/ml as ideal (2, 5). 25(OH)D3 is metabolized in various tissues (predominantly the kidneys) to the biologically most active vitamin D hormone calcitriol (1,25-dihydroxyvitamin D or 1,25(OH)2D3) with another hydroxylation at the 1α position by CYP27A1 or CYP27B1 (3, 4). Besides regulating calcium metabolism, 1,25(OH)2D3 has multiple pleiotropic effects, particularly within the immune system, and is increasingly utilized not only within prophylaxis, but also within therapy of various diseases (2, 6, 7). In particular, binding of 1,25(OH)2D3 to the vitamin D receptor (VDR) has been shown to inhibit the differentiation and proliferation of B and T helper (Th) lymphocytes, promoting the shift of an inflammatory to a more tolerant immune status which may explain the protective effects of vitamin D against autoimmune diseases [reviewed in (8)].
More recently, Slominski and colleagues have revealed alternative pathways of vitamin D metabolism mediated by the mitochondrial enzyme CYP11A1 which is able to hydroxylate the side chain of vitamin D2/D3 (9–11). The main product of these reactions is 20-hydroxyvitamin D3 (20(OH)D3), which has a 20-30-fold lower concentration than 25(OH)D3 in human serum (9, 11) and is the initial substrate for the formation of further hydroxy-derivatives such as 20,23(OH)2D3, 17,20,23(OH)3D3 or 20,22(OH)2D3 [reviewed in (12)]. These nonclassical vitamin D metabolites also act as hormones: besides being partial agonists of the VDR, they have high affinity as agonists of the aryl hydrocarbon receptor (AhR) (13) and as inverse agonists of the retinoid-related orphan receptors (ROR) α and γ (14, 15). Notably, CYP11A1 is expressed in immune cells (16) and RORα and RORγ are expressed by inflammatory Th17 cells in which they synergistically regulate differentiation and inflammatory cytokine production (17). Th17-derived cytokines, notably interleukin (IL)17, have been implicated in the etiology of autoimmune disorders such as psoriasis (18) and multiple sclerosis (MS) (19). In addition, single nucleotide polymorphisms (SNPs) of the RORA gene have been associated with MS (20). The binding of 1,25(OH)2D3, 20(OH)D and other vitamin D hydroxy-metabolites to both RORα and RORγ, result in IL17 inhibition (14), thus providing another mechanism distinct from VDR signaling how vitamin D may protect from, or alleviate symptoms of, autoimmune diseases.
For approximately 15 years, patients with autoimmune diseases, particularly MS, have been successfully treated using a high-dose vitamin D protocol. Because this method has been developed by Prof. Dr. Cicero Coimbra in Sao Paolo, Brazil, it is frequently referred to as the “Coimbra protocol”; in Germany it is utilized since 2016. Underlying the Coimbra protocol is the hypothesis of a non-hereditary, but acquired form of vitamin D resistance which this paper is going to examine.
A hallmark of acquired vitamin D resistance, if it exists, would be an elevated parathyroid hormone (PTH) concentration despite 25(OH)D3 levels being in the ideal range and thus indicating sufficient production of 1,25(OH)2D3. One key role of 1,25(OH)2D3 is to enhance intestinal calcium absorption. If ionized calcium concentrations in blood are low, the parathyroid glands release PTH which stimulates calcium release from bones. Furthermore, PTH increases the conversion of 25(OH)D3 into 1,25(OH)2D3 in the kidneys with subsequent release into circulation. PTH also inhibits the tubular reabsorption of phosphate which in turn lowers the amount of water-insoluble calcium-phosphate salts and thus increases ionized calcium concentrations. In this way, PTH constitutes a direct feedback mechanism within the vitamin D system. A physiological 25(OH)D3 level should thereby be able to suppress PTH into the lower third of the reference range. In other words: If 25(OH)D3 levels are high, PTH should be low and vice versa. In patients with autoimmune diseases this negative feedback loop is disturbed. Based on these observations, Prof. Coimbra proposed the hypothesis of a vitamin D resistance.
The Hypothesis of Acquired Vitamin D Resistance
Com a colaboração de Gustavo Bueno Bellini
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Dr. Cícero Galli Coimbra, MD, PhD, Professor Livre - Docente - CREMESP 55714 - Responsável pela criação e administração deste Site informativo de publicações científicas: Dr. Celso Galli Coimbra, OABRS 11352 